Investigating the role of histone deacetylase inhibitors in enhancing the anti-tumor activity of oncolytic vesicular stomatitis virus

Abstract

Oncolytic virotherapy (OV) is an innovative alternative to conventional cancer therapies based on the concept of selecting or engineering viruses to preferentially replicate in and kill tumor cells by exploiting their genetic defects. Intra-tumoural innate immunity plays a significant role in blocking the effective therapeutic spread of OV. Histone deacetylase inhibitors (HDIs) are known to blunt cellular anti-viral response. This research demonstrates that HDIs enhance the sensitivity of various cancer cell lines to the replication and spread of three different OV platforms---vesicular stomatitis virus (VSV), semliki forest virus (SFV) and vaccinia. The increased oncolytic activity of VSV correlated with a dampening of cellular interferon responses and augmentation of virus replication. Enhancement of virus replication post HDI treatment was also observed in multiple primary human tumor explants as well as in tumor bearing in vivo models. These results illustrate the general utility of HDIs as chemical switches to regulate cellular innate antiviral responses and to provide controlled growth of therapeutic viruses within malignancies.